A multidisciplinary effort is underway to design and synthesize (a) an antineoplastic agent effective against slow growing tumors, and (b) a radiosensitizing agent to selectively sensitize hypoxic tumor cells towards treatment with radiation. Triphenylphosphine gold complex of thymidine has been shown in our preliminary experiments to possess potent antineoplastic activity against P388 leukemia and B16 melanoma. Attempts will be made to delineate the biochemical mechanism(s) of action of this agent, and to design and synthesize a series of purine and pyrimidine analog complexes to increase the antineoplastic activity. The agents synthesized in this program will be tested for antineoplastic activity in a wide spectrum of rodent neoplasms, particularly in slow growing tumors. Since introduction of an additional electron affinic group in the 2-nitroimidazole nucleus has been shown in our laboratory to increase the radiosensitizing efficiency, and insertion of an N-oxide function in the side chain at 1 position of 2-nitroimidazole has been shown to reduce the CNS toxicity, efforts will be made to combine these two findings in developing new radiosensitizers. Systematic studies will be made to explore some other nitroaromatic systems for radiosensitization. These agents will be tested in vitro in bacterial as well as mammalian cell systems in tissue culture; experiments will also be conducted for in vivo radiosensitization. Active agents resulting from this program will be studied for pharmacokinetics, toxicity, biochemical mechanisms of drug action, and DNA damage. The results of these experiments should provide the essential information to allow more rational use of a radiosensitizing agent in combination with radiation treatment to increase therapeutic efficacy.